Carvedilol methanesulfonate

ABSTRACT

This invention relates to carvedilol methanesulfonate, compositions containing this compound and methods of using carvedilol methanesulfonate to treat hypertension, congestive heart failure and angina.

This application claims the benefit of Provisional Application No.60/165,545, filed Nov. 15, 1999.

FIELD OF THE INVENTION

This invention relates to a pharmaceutically active compound,compositions containing the compound and methods of using the compoundin the treatment of certain disease states in mammals, in particularman. More specifically, the present invention relates to carvedilolmethanesulfonate, which is the methanesulfonate salt of1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol,compositions containing this compound, and methods of using carvedilolmethanesulfonate to treat hypertension, congestive heart failure andangina.

BACKGROUND OF THE INVENTION

U.S. Pat. No 4,503,067 describes a compound which is known ascarvedilol. This compound is a novel multiple action drug useful in thetreatment of hypertension and angina. Carvedilol is known to be both acompetitive non-selective β-adrenoceptor antagonist and a vasodilator.The vasodilatory actions of carvedilol result primarily fromα₁-adrenoceptor blockade, whereas the β-adrenoceptor blocking activityof the drug prevents reflex tachycardia when used in the treatment ofhypertension. These multiple actions of carvedilol are responsible forthe antihypertensive efficacy of the drug. Also, carvedilol, as aconsequence of its antioxidant action in attenuating oxygen freeradical-initiated lipid peroxidation, is useful in organ protection, inparticular, cardioprotection. Additionally, carvedilol is useful in thetreatment of congestive heart failure.

The currently marketed formulation of carvedilol is a conventional,swallow tablet and prescribed as a twice-a-day medication in the UnitedStates. This formulation is in immediate release form; that is to saythe nature of the formulation is such that by the time carvedilol leavesthe stomach, it is either in solution or it is in the form of asuspension of fine particles, i.e. a form from which carvedilol can bereadily absorbed.

Carvedilol, a free base with one pKa of 7.6, exhibits a predictablesolubility behavior in neutral or alkaline media, i.e. above pH 9.0, thesolubility is relatively low (<1 ug/mL). The solubility increases withdecreasing pH and eventually reaches a plateau with a broad peak (˜0.2mg/mL) at a pH of 4-5. At acidic pHs of 1 to 4 in buffers, thesolubility is limited by the solubility of the protonated form ofcarvedilol or its salt formed in-situ. The hydrochloride salt formformed in-situ in an acidic medium, such as simulated gastric fluid, isless soluble in water than carvedilol itself.

Surprisingly, it has been found that unlike carvedilol or certain saltforms of carvedilol, carvedilol methanesulfonate exhibits a solubilityof >8.0 mg/ml in purified water at 25° C. Thus, carvedilolmethanesulfonate may result in a dosage form from which the drugsubstance becomes available for bioabsorption throughout thegastrointestinal tract. Hence, it may be possible to develop controlledrelease once-a-day (uid) and twice-a-day (bid) dosage forms, delayedrelease or pulsatile release dosage forms. Also, carvedilolmethanesulfonate may be formulated in an injectible form or as atransdermal patch. The high solubility feature of carvedilolmethanesulfonate is particularly important when formulating thiscompound for therapeutic use.

SUMMARY OF THE INVENTION

The present invention provides a novel salt form of carvedilol, namelycarvedilol methanesulfonate.

The present invention also provides pharmaceutical compositionscontaining carvedilol methanesulfonate and the use of this compound inthe treatment of hypertension, congestive heart failure and angina.

DETAILED DESCRIPTION OF THE INVENTION1-(Carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol isknown as carvedilol. This compound has the following structure:

and is claimed in U.S. Pat. No. 4,503,067 (assigned to BoehringerMannheim, GmbH, Mannheim-Waldhof, Fed. Rep. of Germany), issued Mar. 5,1985. Reference should be made to said patent for its full disclosure,including the methods of preparing and using this compound. The entiredisclosure of the '067 patent is incorporated herein by reference.

In accordance with the present invention, it has been unexpectedly foundthat a novel salt form of carvedilol, namely the methanesulfonate salt,exhibits a significantly higher aqueous solubility than thecorresponding free base or other prepared salts. The aqueous solubilitydata for carvedilol and its salt forms determined at 25° C. arepresented in Table 1.

TABLE 1 Aqueous Solubility (mg/mL) at 25° C. for Carvedilol and its SaltForms Carvedilol Methanesul- Time, hr (ug/mL)* Hydrochloride AdipateTartrate fonate 0.5 5.0 1.65 0.46 0.71 8.17 1 9.8 1.63 0.42 0.70 8.40 41.37 0.25 0.56 8.67 24 11.6 8.70 70 1.06 0.28 0.68 11.2 *Note: thesolubility of carvedilol is given in micrograms per milliliter.

The data from Table 1 demonstrates that the methanesulfonate salt ofcarvedilol exhibits an aqueous solubility in excess of 8 mg/ml, whilethe hydrochloride, adipate and tartrate salt forms are poorly soluble inwater. Thus, the methanesulfonate salt of carvedilol provides for thedevelopment of bioenhanced dosage forms and patient-compliant injectibledosage forms.

Carvedilol methanesulfonate salt form can be formulated in accordancewith the present invention in an injectible form, an oral solid dosageform (as an immediate release or modified release [i.e. controlledrelease, delayed release or pulsatile release] capsule or tablet) or asa transdermal patch, in particular, in pharmaceutical compositions forthe treatment of congestive heart failure, hypertension and angina.

By controlled release is meant any formulation that achieves slowrelease of drug over an extended period of time. In the controlledrelease formulations of the instant invention, a portion of thecarvedilol methanesulfonate in the formulation is made available as apriming dose and the remainder is released in a sustained fashion.Examples of controlled release systems are a matrix tablet or beadformulation, and a barrier film coated tablet or bead/pelletformulation.

By delayed release is meant any formulation wherein the release of thedrug is delayed for certain time or minimum under acidic conditions butrapid above a certain pH depending on the polymer used for the barrierfilm coat. Examples of delayed release systems include timed-releasetablets and capsules and enteric-coated tablets and beads.

By pulsatile release is meant any multi-unit tablet or capsuleformulation where in individual mini-tablets orparticulates/pellets/beads are polymer barrier film coated, thatutilizes intermittent pulsatile dosings of carvedilol methanesulfonatefrom one or more units as a function of time.

Such modified release formulations are preferably formulated in a mannersuch that release of carvedilol methanesulfonate is affectedpredominantly during the passage through the stomach and the smallintestine to the colon.

Examples of controlled release, pulsatile release and delayed releaseformulations which are suitable for incorporating carvedilolmethanesulfonate are described in:

Sustained Release Medications, Chemical Technology, Review No. 177, Ed.J. C. Johnson, Noyes Data Corporation (1980);

Controlled Drug Delivery, Fundamentals and Applications, 2nd Edition,Eds. J. R. Robinson, V. H. L. Lee, Mercel Dekkes Inc., New York (1987);

Remington's Pharmaceutical Sciences, 16th Edition, Ed. A. Osol, MackPublishing Company (1980); and

Solubility Considerations and Design of Controlled Release Dosage Forms,by G. M. Venkatesh, Polymer Preprint, Volume 40, pp 322, 1999 (AmericanChemical Society).

The process for preparing the solid dosage forms in accordance with thepresent invention may be carried out using a combination of a planetarymixture, a V-blender, a high shear granulator, a fluid bed granulator, aslugging press, a roller compactor, a cummunuting mill, sievingequipment, or a tableting machine. Optionally, the granulation of thehydrated or anhydrous form of carvedilol methanesulfonate, producedusing a conventional dry or wet granulating equipment, is suitable forthe preparation of immediate or modified release dosage forms. Thepreferred unit dosage forms include tablets or capsules. Thecompositions of this invention may be formulated by conventional methodsof admixture such as blending, filling and compressing. Suitablepharmaceutically acceptable carriers for use in this invention includediluents, fillers, binders and disintegrants. An intra-venousformulation is prepared by methods known in the industry.

Immediate and modified release matrix beads may be manufactured using aextrusion-spheronization system. A wet granulated mass suitable forextrusion is prepared by blending the drug, a binder and a diluent or amatrix forming polymer, processing through a extrusion-spheronizationsystem and collecting beads of a desired size fraction. The releaseprofiles of the drug from these beads may further be modified byapplying a barrier film coat. A buffer-based membrane-coated beadformulation may also be manufactured by a slurry-coating process asdiscussed in Pharmaceutical Development and Technology, Volume 3, pp477-485 (1998). Alternately, transdermal patches for administration ofcarvedilol methanesulfonate through the skin at a predetermined rate canalso be manufactured.

Any combination of pharmaceutically acceptable excipients, e.g. buffers,carbohydrates, diluents, fillers, binders and disintegrants, in desiredproportions may be utilized in accordance with the wet or drygranulation process or direct compression formulation of the presentinvention. The excipients commonly used in pharmaceutical industry arewell described in the literature [refer to the Handbook ofPharmaceutical Excipients, A. Wade and P. J. Weller (Editors), AmericanPharmaceutical Association (1994)]. Pharmaceutically acceptable fillersand diluents include, but are not limited to, the following: lactose(hydrous as well as anhydrous), starch [unmodified (corn starch) ormodified (for example, Starch 1500 available from Colorcon)], sucrose,mannitol, sorbitol, cellulose, inorganic sulfates and phosphates.Disintegrants include, but are not limited to, the following: sodiumstarch glycolate, sodium carmellose and crosslinked polyvinylpyrrolidone, and binders include, but are not limited to, the following:gelatin, corn starch, modified starch (Starch 1551, pregelatinizedstarch), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose(HPC), sodium carboxy methyl cellulose, alginic acid, acacia, etc.Examples of excipients suitable for modified release applicationsinclude, but are not limited to, the following: high molecular weightHPMCs, polymethacrylate polymers known as Eudragits, polyethylene oxide,Polyox® (Union Carbide Corporation), modified ethyl cellulose,Surelease® (Colorcon), crosslinked acrylic acid polymers, Carbopol® (BFGoodrich Speciality Chemicals) and waxy materials, such as glycerylbehenate (Compritol®, glyceryl palmitostearate (Precirol®), andGelucires® [all from Gattefosse s.a., France] and carnauba wax.

The matrix formulations of the present invention may be prepared usingthree types of materials: insoluble plastics, hydrophilic polymers orfatty compounds. Plastic matrices include methyl acrylate-methacrylate,polyvinyl chloride and polyethylene. Hydrophilic polymers includemethylcellulose, hydroxypropylmethylcellulose (HMPC) and sodiumcarboxymethylcellulose. Fatty compounds include various waxes such ascarnauba wax and glyceryl tristearate. The most common method ofpreparation is to mix carvedilol with the matrix material and thencompress the mixture into tablets. In the case of wax matrices,carvedilol is generally dispersed in molten wax, which is thencongealed, granulated and compressed into cores. In the matrixformulation containing carvedilol, the priming dose (the portion of thecarvedilol that is immediately available in the formulation) is placedin a coat of the tablet. The coat can be applied by press coating or byconventional pan or air suspension coating.

Delayed release formulations containing carvedilol methanesulfonate maybe prepared either by coating particles or granules or tablets withenteric polymers which are resistant to acids but soluble at alkalinepHs. Examples of enteric polymers are hydroxypropylmethyl cellulosephthalate, cellulose acetate phthalate or butyrate, polyvinyl acetatephthalate, Eudragit L and S polymers. Thus, the release of carvedilolmethanesulfonate can be controlled by adjusting the thickness of thebarrier coat and/or by a proper choice of the enteric polymer. Thecoated particles can be filled into capsules or optionally compressedinto tablets.

The present invention also provides for various combinations ofimmediate release and controlled release forms. For example, theuncoated sustained release matrix core may be in combination with animmediate release form of carvedilol methanesulfonate and/or a coatedmatrix form. The matrix core may be comprised of a multitude of pelletscoated independently with different release-delaying substances, all ofwhich may be combined with uncoated or immediate release forms ofcarvedilol methanesulfonate.

The present invention provides a method of treating hypertension, anginaand congestive heart failure by administering an effective amount of animmediate release or controlled release or delayed release formulationcontaining carvedilol methanesulfonate, or a combination thereof, fortreating hypertension, angina and congestive heart failure. Theformulations of the instant invention may also be used in organprotection, for example, in cardioprotection.

The following examples are illustrative of the instant invention. Theseexamples are not intended to limit the scope of this invention asdefined hereinabove and as claimed hereinbelow.

In Examples 2-5, below, the term “internal granules” means thegranulation obtained by blending and granulating ingredients (drugsubstance and excipients) by a wet or dry granulation process.

EXAMPLES Example 1

Preparation of carvedilol methanesulfonate: Carvedilol was suspended inan aqueous solution of methanesulfonic acid, with the acid being presentat a 1:1 molar ratio. The suspension is vortexed during the addition ofcarvedilol powder. After storage of the suspension for 6-15 hrs, thesuspension is filtered and the solid residue is dried.

Example 2

56.0 parts of carvedilol methanesulfonate, 40 parts of powdered mannitoland 4.0 parts of pregelatinized starch (Starch 1551), a binder aregranulated in a planetary mixer using purified water as the granulatingagent. The moist granulation is wet milled and dried using a fluid beddrier or an appropriate drying device. The dried granulation is milledto produce granules passing through a #30 mesh or appropriate sizesieve. Compression mixes with ingredients as listed in Formulas 1 and 2are prepared by blending and compressed into 30.0 mg (as carvedilol freebase) tablets with a tensile strength in the range of 3-10 kP using atablet press. Tablets of Formulas 1 and 2 disintegrate in less than 2minutes when tested in purified water at 37° C.

Ingredients (mg/tab) Formula 1 Formula 2 Internal granules 68.7  68.7Microcrystalline cellulose — 7.5 Crospovidone, crosslinked PVP 3.6 3.0Magnesium stearate 0.7 0.8 Total 73.0  80.0

Example 3

56.0 parts of carvedilol methanesulfonate, 40 parts of fumaric acid and4.0 parts of PVP, a binder, are dry granulated using a chilsonator, aFitzmill and sieve-shaker to produce granules passing through a #30 meshor appropriate size sieve. Compression mixes with ingredients as listedin Formulas 3 and 4 are prepared by blending and compressed into 30.0 mgtablets of hardness in the range of 5-10 kP using a tablet press.

Formula 4 Ingredients (mg/tab) Formula 3 (DC Formula) Carvedilolmethanesulfonate 38.5 Internal granules 68.7 Microcrystalline cellulose20.5 15.5 Spray dried lactose 26.0 Crospovidone, crosslinked PVP 4.0Magnesium stearate 0.8 1.0 Total 90.0 85.0

Example 4

56.0 parts of carvedilol methanesulfonate, 32.0 partshydroxypropylmethyl cellulose (Methocel E4M, from Dow Chemical Co.), 8.0parts of Methocel E15LV, 4.0 parts crosslinked polyvinylpyrrolidone(Crospovidone) and 4.0 parts of pregelatinized starch (Starch 1551), abinder are granulated in a planetary mixer using purified water as thegranulating agent. The moist granulation is wet milled and dried using afluid bed drier or an appropriate drying device. The dried granulationis milled to produce granules passing through a #30 mesh or appropriatesize sieve. A compression mix is prepared by blending 68.7 parts of thegranulation and 0.8 part of magnesium stearate and compressed into 30.0mg tablets releasing the drug at a predesigned fashion.

Modified Release Formulations

Example 5

80.0 parts of carvedilol methanesulfonate, 5.0 parts ofhydroxypropylmethyl cellulose, and 15% glyceryl behenate (Compritol) areblended, roller compacted, milled using a Fitzmill milled to producegranules passing through an appropriate size sieve. Compression mixeswith ingredients as listed in Formulas 5 and 6 are prepared by blendingand compressed into 30.0 mg tablets. Tablets of Formula 6 disperserapidly in the dissolution medium or on oral administration, and thedrug is released from the granules over a long period.

Ingredients (%) Formula 5 Formula 6 Internal granules 48.1 48.1Microcrystalline cellulose 11.2 33.1 Crospovidone, crosslinked PVP 3.0Magnesium stearate 0.7 0.8 Total 60.0 85.0

Example 6

Tablets of Formulas 1 and 2 are applied a membrane barrier coat usingEudragit RL polymer to provide for a long lasting release profile.Tablets of Formulas 3 and 4 are provided with an enteric coat usingEudragit L30D to produce delayed release dosage forms. A seal-coat andan over-coat are optionally applied to the tablets of theseformulations.

Example 7

80 parts of carvedilol methanesulfonate, 10 parts microcrystallinecellulose and 10 parts of Povidone (PVP) are granulated, extruded andspheronized using microcrystalline cellulose for dusting. Dried beads ofa desired size fraction are also coated with a Surelease formulation toprovide a barrier membrane of different thicknesses. Uncoated and coatedbeads at desired proportions are filled into hard gelatin capsules.

Example 8

Non-pareil sugar seeds are layered with carvedilol methanesulfonate byslurry coating in a fluid bed granulator a suspension of the drug andtalc in an aqueous Povidone solution. The pellets are hot melt coatedwith a waxy formula listed below, and cured for 12 hrs at 40° C.

Pellet % W/W (approx) Non Pareil Seed 39 Carvedilol 49 Povidone 10 Talc2 Coating % w/w Glycerylmonostearate 37 Glyceryldistearate 53 White Wax10

It is to be understood that the invention is not limited to theembodiments illustrated hereinabove and the right is reserved to theillustrated embodiments and all modifications coming within the scope ofthe following claims.

The various references to journals, patents, and other publicationswhich are cited herein comprise the state of the art and areincorporated herein by reference as though fully set forth.

What is claimed is:
 1. A compound which is carvedilol methanesulfonate.2. A pharmaceutical composition comprising the compound according toclaim 1 and a pharmaceutically acceptable carrier.
 3. A controlledrelease formulation comprising the compound according to claim 1 indosage unit form.
 4. A delayed release formulation comprising thecompound according to claim 1 in dosage unit form.
 5. A matrixformulation comprising the compound according to claim 1 in dosage unitform.
 6. An enteric coated formulation comprising the compound accordingto claim 1 in dosage unit form.
 7. A method of treating hypertension,congestive heart failure or angina which comprises administering to asubject in need thereof an effective amount of the compound according toclaim
 1. 8. A process for the preparation of carvedilol methanesulfonatewhich comprises reacting carvedilol with an aqueous solution ofmethanesulfonic acid, with the acid being present at a 1:1 molar ratio.